This invention relates to novel 5-(2-alkoxyphenyl)thiazolidinediones and to pharmaceutically acceptable salts thereof useful as hypoglycemic agents, inhibitors of aldose reductase and as therapeutic agents for the treatment of chronic diabetic complications.
Despite the widespread use of insulin and of the availability of a large number of synthetic hypoglycemic agents such as the sulfonylureas (e.g chlorpropamide, tolbutamide, acetohexamide) and biganides (e.g. phenformin), the search for improved hypoglycemic agents continues. More recently, efforts have been directed to controlling certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy. Such efforts have given rise to development of aldose reductase inhibitors, compounds which inhibit the activity of the enzyme aldose reductase which is primarily responsible for regulating reduction of aldoses to the corresponding polyols. In this way, unwanted accumulation of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, kidney and peripheral nervous cord of various diabetic subjects is prevented or reduced. References which describe aldose reductase inhibitors are U.S. Pat. No. 3,821,383, 1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and related compounds; U.S. Pat. No. 4,200,642 - spiro-oxazolidine-24-diones; U.S. Pat. Nos. 4,117,230; 4,130,714; 4,147,797; 4,210,756; 4,235,911 and 4,282,229 each of which describes certain spirohydantoins. Belgian Pat. Nos. 889,757 and 889,758 describe 5-(substituted phenyl)oxazolidine-2,4-diones as hypoglycemic agents.
European Patent Application 33,617 published Aug. 12, 1981 describes certain 5-(disubstituted phenyl)thiazolidine-2,4-diones which exhibit activity to control chronic diabetic complications. A variety of 5-(4-alkoxybenzyl)thiazolidine-2,4-diones having hypolipidemic and hypoglycemic activities are disclosed in European Patent Application No. 8203 published Feb. 20, 1980.
Sohda et al., Chem. Pharm. Bull. 30,3601-16 (1982) report on the hypoglycemic and hypolipedemic properties of thiazolidine-2,4-diones having at the 5-position one or two substituents such as phenyl, heteryl or alkyl. Many of the same compounds are disclosed in Japanese Patent Application No. 57,028,073, published Feb. 15, 1982.